Since its inception, the primary goal of the Emory Alcohol and Lung Biology Center has been to develop novel and effective treatments that can mitigate or even reverse the pathophysiological effects of alcohol on the lung. The first two funding cycles were dedicated to elucidating the fundamental mechanisms that induce the ?alcoholic lung phenotype?. Our experimental findings have elucidated central roles for oxidative stress (including profound glutathione depletion), zinc deficiency, and decreased expression and function of PPAR? in mediating the effects of alcohol. More recently we identified that alcohol inhibits the actions of Nrf2, the transcription factor that activates the anti-oxidant response element (ARE) and programmatically induces the expression of hundreds of genes (including those involved in glutathione homeostasis) required to defend against inflammatory stresses. Moreover, Nrf2 and PPAR? activity appear to be zinc-dependent and therefore these pathways may be interdependent and therefore coordinately targeted by alcohol. Remarkably, these same pathways are targeted during chronic HIV infection, and we have determined that alcohol and HIV- related proteins have additive toxicities on lung epithelial and macrophage function. As our Center investigators are also engaged in translational clinical trials in HIV-mediated lung disease, we have the unique capacity to study the combined effects of alcohol and HIV and how this combination may pose a challenge to developing effective therapies. These discoveries have not only revealed the mechanisms by which alcohol renders the lung susceptible to injury but have also identified candidate therapies targets that Center investigators are testing in experimental models and clinical trials. This new Project 3 will coordinate and direct our ?clinical trials pipeline? and shepherd discoveries from the laboratory to interventional trials. The goals of Project 3 are to: 1) Determine the efficacy of dietary supplementation with zinc and/or SAMe in reversing the alcoholic lung phenotype in subjects with alcohol use disorders and, in parallel, how regular alcohol use affects the efficacy of dietary zinc + SAMe in reversing lung dysfunction in individuals living with HIV. 2) Exploit our experimental and clinical translational studies on alcohol-induced inhibition of PPAR? signaling to conduct a clinical trial to determine if treatment with the PPAR? ligand pioglitazone can reverse the alcoholic lung phenotype in subjects with alcohol use disorders. 3) In collaboration with Projects 1 and 2, determine if Nrf2 activators, alone or in combination with zinc, can rapidly reverse the alcoholic lung phenotype in animal models in vivo and in human alveolar macrophages ex vivo, and translate these studies to a clinical trial of agents such as sulforaphane, alone or in combination with zinc, in subjects with alcohol use disorders. Success in any of these trials in our pipeline will have enormous implications for individuals struggling with alcohol use disorders, including those also living with HIV.